Targeting Lipid Metabolism in Colorectal Cancer

项目摘要 转移是包括结直肠癌（CRC）在内的实体瘤死亡的主要原因。我们的长期 我们的目标是开发更多的选择性治疗方案，以预防或减少CRC转移的发生率， 了解脂肪酸代谢的变化如何导致转移性疾病。 脂肪酸合成酶（FATCH）是脂质从头合成的关键酶， 在CRC中活化，并且其活性与不良预后、疾病复发和死亡的较高风险相关。 我们将Festival确定为晚期CRC的潜在靶点，并表明该酶的上调是一个潜在的靶点。 支持CRC转移的关键机制。然而，Festival调控的潜在机制， 转移和对FGFAP抑制的抗性的潜在机制尚不清楚。当前应用程序 提出了一项全面的研究计划，研究脂质调节CRC转移的新机制， 新陈代谢.我们的初步数据表明，从头脂肪酸合成的主要产物，棕榈酸酯， 选择性地用于鞘脂合成。过表达FGF 1选择性地调节SphK 1的活性， SphK 2并增加鞘氨醇-1-磷酸（S1 P）的水平，S1 P是一种涉及 转移因此，在目的1中，我们将检验以下假设，即FGFAP通过上调肿瘤细胞的增殖来增强转移。 SphK/S1 P轴，我们将确定SphK 1和SphK 2对CRC转移的贡献。而且我们的 初步研究表明，FXR和CD 36（一种脂肪酸移位酶）的表达之间存在相关性 负责外源性FA摄取。我们的数据显示，Fatty acid的抑制导致CD 36和CD 38的上调。 它可能是对新型FASN抑制剂耐药的潜在机制，目前正在阶段测试 II临床试验。因此，在目标2中，我们将阐明FGFAP如何调节CD 36并确定分子水平。 CD 36的上调有助于CRC转移的机制，包括CD 36 上调鞘脂代谢和S1 P合成。在目标3中，我们将测试抑制FA摄取是否 通过CD 36将增加一种新的FcB抑制剂TVB-3664在CRC中的疗效。 我们将利用来自患者的生物样品、人原代CRC细胞、从大肠癌细胞建立的肿瘤类器官、以及来自大肠癌细胞的肿瘤细胞。 转基因小鼠和CRC转移模型，这是临床前研究的最先进的模型。 目标和药物评价。这些模型将与最先进的方法结合使用，包括 靶向和稳定的同位素分辨代谢组学（SIRM），以评估脂质合成改变的影响 和FA摄取对癌细胞代谢的影响。这些研究具有很高的翻译影响，因为CD 36和FXR 抑制剂目前在多个临床前研究和I-II期临床试验中进行了测试， 更多关于其在CRC中的作用的研究和知识。除了验证FXR、SphKs和CD 36作为 CRC的治疗靶点，代谢和信号通路的综合分析， 目前的应用也有可能确定新的药物靶点和CRC的治疗策略。

PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However, the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid implicated in metastasis. Therefore, in Aim 1, we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore, our preliminary studies show a correlation between expression of FASN and CD36, a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore, in Aim 2, we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3, we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients, human primary CRC cells, tumor organoids established from genetically modified mice and CRC metastasis models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including targeted and stable isotope-resolved metabolomics (SIRM), to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN, SphKs and CD36 as therapeutic targets in CRC, the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.